1. Field of Invention
This invention is directed to kits, compositions and methods of identifying neurological, neuropsychological, neuropsychiatric, behavioral and cognitive functions in the central nervous system, PKCg biomarkers directed to non-ischemic events.
2. Description of the Background
The events of ischemia include hypoxia and hypoglycemia due to the reduction or elimination of blood flow through affected tissues. However, hypoxia also occurs under conditions of normal or even increased cerebral blood flow.
The effects of hypoxia on central nervous system functions, such as short-term memory loss and the impairment of cognition and performance tasks have been studied through a variety of experimental approaches and models. Neurological, neuropsychological and psychometric tests have been used to assess central nervous system function. Additionally, dysfunctions of the cerebellum include cognitive affective syndrome, ataxia, and dysmetria of thought. Considerable efforts are underway to clarify the cellular and molecular mechanisms contributing to these processes. The gamma isoform of protein kinase C (PKCg) is unique to the central nervous, including the eye. Although broadly distributed throughout the brain, PKCg is concentrated in the hippocampus and cerebellum, structures associated with information processing such as learning and cognition. In ischemia, PKCg has been found in samples of peripheral blood (see U.S. Pat. No. 6,268,223); however, hypoxia occurring under conditions of normal or even increased cerebral blood flow has not heretofore been studied in detail.
Acute mountain sickness is among the most prominent pathophysiological conditions related to hypoxia at high altitudes and is characterized by a range of neurological impairments. Table 1 depicts physiological variables in healthy subjects at sea level and at high altitude. If not effectively treated, high altitude cerebral encephalopathies (HACE), a potentially lethal condition, ensue.
TABLE 1Central Hemodynamic, Blood Gases, and Transcranial DopplerVariables in 35 Healthy Subjects at Sea Level and atHigh Altitude. (Cf. Van Osta)Sea LevelAltitudePHR, bpm76 ± 2085 ± 12<0.05Sao297 ± 1 79 ± 7 <0.001Pao2, mm Hg90 ± 1141 ± 6 <0.001Paco2, mm Hg40 ± 2 30 ± 2 <0.001Systolic BP, mm Hg137 ± 20 137 ± 26 NSDiastolic BP, mm Hg81 ± 1282 ± 17NSMean BP, mm Hg100 ± 14 100 ± 18 NSSystolic Vmca, cm/s69 ± 1172 ± 18NSDiastolic Vmca, cm/s34 ± 7 37 ± 13NSMean Vmca, cm/s49 ± 8 52 ± 14NSARI4.44 ± .0864.55 ± 1.16NSData are given as mean ± SD.
Table 2 depicts hypoxic thresholds for central nervous system dysfunctions at sea level and simulated altitudes causing hypoxia.
TABLE 2Hypoxic Thresholds for CNS Dysfunction (Values derived fromyounger volunteers subjected to acute (minutes) decompressionhypoxia. FiO2, fractional percentage of ambient oxygen.(Cf. Bailey; Butterworth; Huff; Kirkham & Datta)Simulated altitude (ft)FiO2 (%)PaO2 (mm Hg)Neurological statusSea level2190Normal 5,0001780Impaired dark vision 8,000-10,00015-1455-45Impaired short-termmemory, difficultylearning complextasks15,000-20,00011-9 40-30Loss of judgment,euphoria,obtundation>20,000<9<25 Coma
Retinal encephalopathies also occur at these altitudes and include torturous, leaky vasculature consistent with established physical symptoms of HACE. These are clear examples of hypoxic encephalopathies at partial pressure of oxygen; PKCg is present in samples of peripheral blood during hypoxic encephalopathies. These same oxygen pressures elicit short-term memory impairment, difficulty learning complex tasks, loss of judgment, euphoria, and obtundation.